MALT LYMPHOMA, GASTROINTESTINAL STROMAL TUMOR.

CLINICAL PRESENTATION. Most patients are asymptomatic, and their small indolent tumors (<2 cm in diameter) are often discovered incidentally. For example, GISTs can be detected during an endoscopic study. Other patients with indolent endoluminal progression of the primary tumor may present with nonspecific chronic symptoms (e.g., early satiety or bloating). • However, some tumors may eventually grow large enough (>6 cm) to present with symptoms. The most common symptoms include:

(i) bleeding, (ii) symptoms associated with an abdominal mass and (iii) obstructive symptoms. • Bleeding may take place either in the gastrointestinal tract lumen causing hematemesis, melena and anemia or into the abdominal cavity causing acute abdominal pain and severe anemia. • Symptoms associated with an abdominal mass include abdominal pain, anorexia, nausea, vomiting, weight loss, and epigastric fullness. • The obstructive symptoms are site-specific (dysphagia with an esophageal GIST, constipation with a colorectal GIST, obstructive jaundice with a duodenal tumor). • Physical examination may identify a palpable mass in the abdomen.

The t(11;18)(q21;q21) is the most common, identified in up to

50% of gastric MALT lymphomas. The t(11;18) translocation fuses the BIRC3 gene (formerly termed API2: apoptosis inhibitor-2 gene) on chromosome 11 with the MALT1 gene on chromosome 18, while the t(14;18)(q32;q21) fuses MALT1 with the IgH gene on chromosome 14. The t(1;14)(p22;q32) fuses the BCL10 gene on chromosome 1 to the IgH gene promoter. MALT1 and BCL10 proteins synergize in the activation of NF-κB. These 3 translocations result in constitutive activation of nuclear factor kappa B (NF-κB). NF-κB is a transcription factor that regulates multiple aspects of innate and adaptive immune functions and serves as a pivotal mediator of inflammatory responses. NF-κB induces the expression of various pro-inflammatory genes, including those encoding cytokines and chemokines, and also participates in inflammasome regulation.

Immunophenotype. There is no specific marker for MALT lymphoma. The tumor cells express B cell-associated markers

CD19, CD20, CD22, which are transmembrane proteins expressed on the surface of all B-cells. The tumor cells are negative for T cell markers. • The tumor cells express surface membrane immunoglobulin (Ig). The demonstration of Ig light chain restriction is important in the differential diagnosis with benign lymphoid infiltrates. While benign (reactive) B-lymphocytic populations produce Ig-molecules containing an almost equal amount of kappa and lambda light chains, i.e., the number of cells producing kappa is more or less equal to the number producing lambda, neoplastic B-lymphocytic populations demonstrate light chain restriction (i.e., are monoclonal) producing either kappa or lambda, but not both.

Campylobacter jejuni is cultured from the stool and 16S rDNA Campylobacter sequences are detected in the small intestinal tissue biopsy samples of patients with

IPSID. C. jejuni behaves in IPSID as does H. pylori in gastric MALT lymphoma, as a continuous antigenic trigger favoring lymphoproliferation. C. jejuni is a helical-shaped, Gram-negative, microaerophilic bacterium with a single flagellum at one or both poles. C. jenuni is one of the most common causes of acute gastroenteritis in the United States, characterized by diarrhea, fever, and abdominal cramps.

MALT lymphoma of the small intestine. Immunoproliferative small intestinal disease (IPSID) is the term adopted by WHO for

MALT lymphoma of the small intestine. IPSID has been previously known as Mediterranean lymphoma or alpha chain disease.

H. pylori infection is highly associated with the development of

MALT lymphoma of the stomach. Most patients (>90%) with gastric MALT lymphoma are H. pylori positive. Under physiological conditions, the stomach mucosa does not contain lymphoid tissues. Antigens derived from H. pylori drive the activation of T cells, B cell proliferation, and lymphoid follicle formation, which if persistent can evolve into a monoclonal lymphoma. • A main role is played by the H. pylori cytotoxin-associated gene A (CagA) protein, also involved in gastric cancer pathogenesis. Serum anti-CagA antibody is positive in more than 95% of patients suffering from gastric MALT lymphoma, and the CagA protein is detected in MALT lymphoma cells. • Eradication of H. pylori with antibiotics results in regression of MALT lymphoma in more than 75% of cases, indicating that the early stage of MALT lymphoma is still dependent on antigen-stimulation. The accumulation of genetic abnormalities in the B cells induced by this chronic inflammation is associated with both a loss of dependency from antigenic stimulation (with subsequent antibiotic resistance).

Gastric MALT lymphoma is a low grade (indolent) lymphoma that is usually at

Stage I when diagnosed and is slow to disseminate. Eradication of H. pylori infection results in durable complete remission in a high percentage of cases. Transformation to an aggressive lymphoma (diffuse large B‐cell lymphoma) occurs in a small percentage of cases

Lymphomas are

a heterogeneous group of malignancies that arise from lymphocytes

Appendiceal NETs are mostly discovered coincidentally during

appendectomy. The majority are located in the distal one-third of the appendix, where they are unlikely to cause obstruction; they usually show a benign clinical course. A few are located at the base of the appendix, where they can cause obstruction leading to appendicitis. Carcinoid syndrome is very uncommon. Most of appendiceal NETs are small and have a low metastatic potential.

Clinical presentation. Patients with gastric MALT lymphoma can be

asymptomatic or experience epigastric pain or discomfort, anorexia, weight loss, nausea and/or vomiting, occult gastrointestinal bleeding, and early satiety. The duration of symptoms preceding the diagnosis ranges from a few days to 6 years. The physical examination is often normal but may reveal a palpable mass. Laboratory studies also tend to be normal at presentation.

Gastric NETs. Most of gastric NETs are associated with

autoimmune gastritis and Zollinger-Ellison syndrome. These tumors are derived from enterochromaffin-like (ECL) cells stimulated by elevated serum gastrin levels. They are well differentiated and usually indolent and nonfunctioning tumors. • A second type of gastric NETs occurs in the absence of a preexisting gastric condition. The fasting serum gastrin is normal. These tumors are aggressive with hepatic metastases present in most patients at diagnosis. They are functional and may be associated with carcinoid syndrome.

Grossly, gastric MALT lymphomas assume several patterns:

benign-appearing gastric ulcer, thickened cerebroid gastric folds, nodularity of the mucosa, and polypoid lesion. • Histologically, gastric MALT lymphoma takes the form of a dense lymphocytic infiltrate in the lamina propria. The lymphoma cells infiltrate and destroy adjacent gastric glands to form characteristic lymphoepithelial lesions. Lymphoepithelial lesions are defined as infiltration of the glandular epithelium by clusters of neoplastic lymphoid cells with associated destruction of gland architecture and eosinophilic degeneration of the epithelial cells. • Adjacent reactive germinal centers composed of non-neoplastic reactive lymphoid follicles may be present.

Well-differentiated NETs often retain their ability to secrete nonhormonal secretory products such as

chromogranin, serve as circulating serum tumor markers. • These markers are not useful as a diagnostic test: they are not specific for neuroendocrine tumors. Hypertension, heart failure, acute coronary syndrome, renal insufficiency, inflammatory bowel diseases, and chronic hepatitis are associated with elevated chromogranin levels. • Serum levels of chromogranin fluctuate without corresponding changes in clinical status and increase significantly during proton-pump inhibitor (PPI) treatment. • Elevated urinary levels of 5-HIAA are highly sensitive and specific for small intestinal tumors that have metastasized to the liver and produce the carcinoid syndrome. • The histological diagnosis of neuroendocrine neoplasms is confirmed by immunohistochemical demonstration of neuroendocrine markers. Several general neuroendocrine markers are known: chromogranin, synaptophysin, and neuron-specific enolase. Chromogranin and synaptophysin are the most common markers to confirm the endocrine nature of the neoplastic cells.

Poorly differentiated neuroendocrine carcinomas (NECs). Poorly differentiated NECs have an aggressive natural history that is characterized by

early, widespread metastases. About 60% of patients have metastases at diagnosis. These tumors are non-secretory and show similarities in morphology, biologic behavior, and chemotherapy responsiveness to poorly differentiated (small cell and large cell) NECs of the lung. • Unlike patients with well-differentiated NETs who typically present with a relatively indolent disease process and who have a good chance of cure with full surgical resection, patients with poorly differentiated NECs may seem to be acutely ill and have a more rapidly evolving disease course. • Well-differentiated NETs have a better prognosis than conventional adenocarcinomas, whereas poorly differentiated NECs carry a very poor prognosis compared to conventional adenocarcinomas.

Duodenal NETs. Two distinct types of duodenal NETs are recognized:

gastrinomas and somatostatinomas. Gastrinomas produce the clinical manifestations of Zollinger-Ellison syndrome. Duodenal somatostatinomas are not functional and cause symptoms by local mass effect: abdominal pain and biliary obstruction (jaundice).

Poorly differentiated neuroendocrine carcinomas (NECs). Grossly, poorly differentiated NECs are

large, often ulcerated masses as in conventional adenocarcinoma. Microscopically, poorly differentiated NECs are classified as small-cell carcinomas or large-cell carcinomas. The basic histological features of small-and large-cell carcinomas of the gastrointestinal tract are similar to those of the lung. • Poorly differentiated NECs are characterized by a mitotic rate of >20 mitoses per 10HPF and Ki-67 index of >20%. These tumors are grade 3 by definition and therefore do not require formal grading.

Large-cell carcinomas are composed of

large-sized tumor cells possessing abundant cytoplasm, large vesicular nuclei with variably coarse chromatin, prominent nucleoli, and necrosis. Cells are arranged in a sheet-like, organoid nesting, or trabecular pattern.

Nodal lymphomas originate in

lymph nodes, or from other lymphoid tissues such as spleen, thymus, bone marrow, and Waldeyer's ring. Nodal lymphomas account for about 70% of all lymphomas.

• MALT is populated by

lymphocytes such as T cells and B cells, as well as plasma cells and macrophages, each of which is well situated to encounter antigens passing through the mucosal epithelium. About half the lymphocytes of the body are in the MALT. • The main function of MALT is to be on the alert for any invading pathogens. MALT tissues serve as antigen presentation sites in non-lymphoid peripheral organs. MALT cells produce and secrete IgA across mucosal surfaces in antigen specific, Th2-dependent reactions

MALT lymphomas are a category of non-Hodgkin lymphomas that arise from

mature B lymphocytes. Most MALT lymphomas are found in the gastrointestinal tract. The most common site is the stomach, followed by the small intestine, whereas colon MALT lymphomas are rare. Gastric MALT lymphoma is the best studied and is, therefore, the paradigm for the MALToma group as a whole. MALT lymphomas account for 8% of all non-Hodgkin lymphomas. These tumors are mainly seen in adults with a median age at diagnosis of 66 years. Men are more commonly affected by MALT lymphoma of the stomach, small intestine and the skin, whereas women are more commonly affected by MALT lymphomas of the salivary glands and thyroid.

Gastrointestinal stromal tumors (GISTs) are

mesenchymal neoplasms of the gastrointestinal tract and are thought to develop from the pluripotential mesenchymal stem cell programmed to differentiate into the interstitial cell of Cajal (ICC). • Derived from mesoderm, ICC located within the muscularis propria generate spontaneous electrical activities which spread passively via gap junctions to neighboring smooth muscle cells and produce spontaneous contractions such as peristalsis. • ICC express c-KIT, a receptor tyrosine kinase, on the plasma membrane and c-KIT immunostaining is used to label the ICC network.

Microscopically, well-differentiated NETs are composed of tumor cells possessing round or oval nuclei with "salt and pepper" (i.e., granular, not solid) chromatin and eosinophilic granular cytoplasm. Well-differentiated NETs show one of the following growth patterns:

nesting (nodular), insular (tightly packed islands of cells separated by a negligible stroma), trabecular (cord-like arrays separated by fibrous septa), gyriform (undulating single-file rows of tumor cells), or sometimes, acinar (glandular) patterns. Microscopic patterns have no prognostic significance, and a tumor can have mixed patterns. Well-differentiated NETs are classified into one of three grades based on mitotic count and Ki67 proliferation index. • Grade 1: < 2 mitoses per 10 HPF and Ki-67 index <3%. • Grade 2: 2-20 mitoses per 10 HPF and Ki-67 index 3-20% • Grade 3: >20 mitoses per 10 HPF and Ki-67 index of >20%. With expansion and infiltration into the muscularis propria and serosa, carcinoid tumors involve the mesentery. Mesenteric lymph nodes and liver are sites of metastases.

NENs are epithelial neoplasms with predominant

neuroendocrine differentiation. As neuroendocrine cells are ubiquitous in our body, NENs can form in different organs. Most of the NENs are in the gastrointestinal tract (55%) or in the bronchial tree (25%). • Neuroendocrine cells in the gastrointestinal tract consist of less than 1% of the mucosa. They are normally distributed at the surface or base of glandular epithelial cells, such as the gastric pits of the stomach and the crypts of the small intestine and colorectum; and contain secretory granules that release various peptide hormones and biogenic amines. • The localization of gastrointestinal NENs is as follows: small intestine (45%), rectum (20%), appendix 16%), colon (11%), and stomach (7%).

NETs of the transverse and descending colon and rectum are

nonsecretory and not associated with carcinoid syndrome, even when metastatic. These tumors are discovered at earlier stages due to colon cancer screening programs. The vast majority of them are asymptomatic when found incidentally on endoscopy. When symptoms do occur, they are the same as those of a colorectal adenocarcinoma: changes in bowel habits, obstruction, or bleeding. Most of them are localized at diagnosis. The metastatic potential is low.

Small intestinal NETs present with

paroxysmal abdominal pain and intermittent bowel obstruction, which are due intense desmoplastic reaction (i.e., fibrous tissue formation), which tends to cause kinking of the bowel leading to obstruction and local ischemia with perforation. The majority of patients have metastases at diagnosis, even when the primary tumor is small. • Patients with liver metastases tend to develop carcinoid syndrome, which is caused by the secretion of hormones, including serotonin, histamine, tachykinins, kallikrein, and prostaglandins. Most of these hormones enter the portal circulation and are inactivated by the liver; consequently, the classical carcinoid syndrome is rarely seen in the absence of metastatic disease. The carcinoid syndrome consists of flushing, diarrhea, valvular heart disease, and bronchospasm, in order of decreasing frequency. • Urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) which is the end product of serotonin metabolism is markedly increased in patients with carcinoid syndrome.

Interstitial cells of Cajal express c-KIT. Like normal Cajal cells, GISTs also express c-KIT. • The c-KIT is a

receptor tyrosine kinase whose activity is normally regulated by binding an endogenous ligand known as stem cell factor. Binding of stem cell factor to c-KIT results in receptor homodimerization, activation of its tyrosine kinase activity and phosphorylation of downstream substrates leading to signal transduction. • A gain-of-function mutation in the c-KIT gene has been identified in about 80% of GISTs, leading to constitutive activation of the receptor. About 8% of GISTs do not express c-KIT but have mutations that activate the related receptor tyrosine kinase, platelet-derived growth factor receptor α (PDGFRA). Constitutively active KIT and PDGFRA trigger the same downstream signaling pathways.

Extranodal lymphomas, by definition, involve

sites other than lymph nodes, spleen, thymus and Waldeyer's ring. Involvement of the spleen in Hodgkin lymphoma is considered as nodal disease but in the case of non-Hodgkin lymphoma the spleen is regarded as an extranodal site. Extranodal lymphomas originate most commonly from the gastrointestinal tract and the skin, but any organ can be involved.

• Small-cell carcinomas consist of

small, round, ovoid or spindle-shaped tumor cells with scant cytoplasm and hyperchromatic nuclei with indistinct nucleoli. They are mainly arranged in a sheet-like pattern. Large areas of necrosis are common.

Neuroendocrine neoplasms (NENs) arise from

the diffuse system of neuroendocrine cells i.e., cells with features of both nerve cells (which can receive message from the nervous system) and endocrine cells (which synthesize and secrete monoamines, peptides and hormones). Neuroendocrine cells do not have any axons or nerve terminals. The electrical signals from the nervous system are converted into hormonal signals with production of hormones, peptides and amines.

Mesenchymal tumors are rare in the gastrointestinal tract. Gastrointestinal stromal tumors (GIST) represent

the largest fraction of all gastrointestinal mesenchymal tumors (80%). Once thought to be smooth muscle tumors, GISTs are now thought to differentiate along the lines of interstitial cells of Cajal, the pacemaker cells of the gastrointestinal tract. Leiomyomas, lipomas, schwannomas, neurofibromas, and synovial sarcomas are very rare neoplasms in this location

Mucosa-associated lymphoid tumor (MALT) lymphoma, also referred to as "MALToma," is a type of extranodal lymphoma. MALT lymphoma affects

the mucosa-associated lymphoid tissue (MALT), a diffuse system of small concentrations of lymphoid tissue found in various submucosal membrane sites of the body, such as the gastrointestinal tract, nasopharynx, bronchi, and skin. The tonsils, Peyer patches within the small intestine, and the vermiform appendix are examples of MALT. MALT has been described in conjunctiva, larynx, lacrimal duct, and salivary glands as well.

Deregulated NF-κB activation contributes to

the pathogenic processes of various inflammatory diseases and neoplasms. NF-κB stimulates cell proliferation and prevents apoptosis. NF-κB induces the expression of genes (cyclins, cyclin-dependent kinases) that initiate cell division and genes that block the apoptotic pathway.

Immunohistochemically, the vast majority of GISTs (95%) are strongly and diffusely positive for

the receptor tyrosine kinase c-KIT (CD117), which makes the c-KIT to be a very specific and sensitive marker in the differentiating GIST from other mesenchymal tumors in the gastrointestinal. The stain appears as cytoplasmic. A small proportion (5%) of GISTs are c-KIT-negative. The other mesenchymal tumors of the gastrointestinal tract are typically c-KIT negative.

GISTs occur throughout the gastrointestinal tract from the esophagus to the anus, but they are most common in

the stomach (60%) and jejunum/ileum (30%). Only 10% of GISTs are found in the esophagus, mesentery, omentum, colon, or rectum. 3. Biologic behavior. GISTs vary in malignancy potential ranging from small, slow growing, incidentally detected benign tumors with excellent outcome to aggressive sarcomas with the propensity to invade adjacent organs, metastasize to the liver, and recur locally within the abdomen. The malignant GISTs account for 20-35% of all GISTs.

PATHOLOGY. GISTs are well-circumscribed firm white masses within the wall of the stomach or intestine and surrounded by a pseudocapsule. Most are between 5 cm and 10 cm at diagnosis. They arise from the muscularis propria and extend inward toward the mucosa, outward toward the serosa, or in both directions. Large GISTs often show

ulceration, cystic degeneration or central necrosis. • Microscopically, GISTs are divided into three principal subtypes: spindle-shaped (70% of cases), epithelioid (20%), and mixed (10%). The cell type influence on the outcome is not relevants. • The spindle-shaped type is composed of bland spindle cells with faintly eosinophilic cytoplasm in a syncytial pattern. Nuclei are elongated with inconspicuous nucleoli cells. Extracellular deposits of dense collagen are also seen. The cells are arranged in short fascicles or whorls. • The epithelioid type is composed of round cells with clear to eosinophilic cytoplasm and round nuclei arranged in sheets or nests. • The mixed type is composed of cells with spindle and epithelioid morphology. • The distinction between benign and malignant depends on the presence of nuclear atypia and presence of necrosis, hemorrhaging, and mitotic activity.

The majority of IPSID cases reported are from the Mediterranean region and Middle East. Sporadic cases of IPSID have rarely been reported from North America. • IPSID affects mainly adolescents and young adults (age range 10-35) with a male predominance of 2:1. • Common sites of involvement are

upper jejunum and the 2nd to 4th parts of the duodenum. The histopathology of the IPSID and H. pylori-associated gastric MALT lymphoma are similar: the mucosa of the intestine shows a diffuse infiltration by lymphocytes and plasma cells, and lymphoepithelial lesions.

Well-differentiated neuroendocrine tumors (NETs). Well-differentiated NETs were traditionally referred to as carcinoid tumors. The term carcinoid is not preferred because it does not convey the potential for malignant behavior that accompanies these neoplasms. Well-differentiated NETs are

whitish to yellowish solid tumors with a nodular or polypoid appearance. The overlying mucosa is generally intact or shows slight focal ulceration because the tumor mass is deep in the mucosa.

IPSID patients present with a malabsorption syndrome characterized by abdominal pain, diarrhea, weight loss, hypoproteinemia and electrolyte derangements due to chronic diarrhea. • Laboratory studies show elevation of

α-heavy chain protein in up to 90% of cases. The α-heavy chain is a monoclonal protein consisting of a portion of the immunoglobulin heavy chain without a bound light chain. A truncated α-heavy chain results from structural mutation of the immunoglobulin heavy chain. The mutant α-heavy chain is incapable of either partnering with light chains in the formation of a full immunoglobulin molecule or of being degraded by the proteasome. • Antibiotics active against C. jejuni are effective against IPSID in the early stages, as they are for H. pylori-related gastric MALT lymphoma. Transformation to diffuse large B cell lymphoma may occur.